Local control with definitive radiotherapy in locally advanced non-small cell lung cancer (NSCLC) is extremely poor with biopsy proven local failure rates at one year as high as 80%. This is likely due to significant tumor resistance to radiotherapy. Inhibitors of the vascular endothelial growth factor (VEGF) signaling pathway have been shown to function as radiation sensitizers both in vitro and in vivo. One hypothesis for the mechanism of this radiation sensitization is that VEGF inhibition prunes immature vasculature, resulting in normalization of tumor blood flow, which in turn allows for increased oxygen delivery to the tumor. The increase in tumor oxygenation results in enhanced reactive oxygen species formation in response to ionizing radiation allowing for greater DNA damage. This hypothesis is supported by the observation that patients with improved tumor hemodynamics after radiotherapy as quantified by dynamic contrast enhanced imaging have an improved response to treatment. Our group and others have shown that Nelfinavir modulates VEGF signaling and improves tumor perfusion and oxygenation in animal models. We also have preliminary clinical data using DCE-MRI that suggests a decrease in tumor vascular permeability with administration of Nelfinavir, suggestive of blood flow normalization. We have recently completed a phase I trial of Nelfinavir with concurrent chemoradiotherapy in patients with locally advanced NSCLC. We observed a promising 100% overall response rate, 58% complete metabolic response rate, and local control rate of 92% with 13 months follow-up in these patients. Our hypothesis to explain these clinical results is that Nelfinavir administration results in radiosensitization of NSCLC through vascular normalization. We therefore propose to utilize DCE-MRI tumor imaging to assess vascular normalization in patients with locally advanced NSCLC in response to treatment with Nelfinavir. The overall objective of this project is to determine whether Nelfinavir administration results in decreased vascular permeability in patients with locally advanced NSCLC and to determine if this decrease correlates with clinical outcome. Finally, we will explore the relationship between the magnitude of the permeability response to chemoradiotherapy in patients receiving Nelfinavir and tumor response to treatment. In doing this we will explore the fundamental question: Can Nelfinavir favorably alter the tumor microenvironment in locally advanced NSCLC to overcome extrinsic tumor resistance to definitive chemoradiotherapy? PUBLIC HEALTH RELEVANCE: Lung cancer exacts a devastating impact on public health with 200,000 new cases each year with approximately 175,000 deaths. Greater than 50% of patients with lung cancer receive definitive radiotherapy;however, the majority of these patients are not cured with almost 60-80% of patients experiencing a relapse of their disease. The purpose of this project is to determine whether dynamic contrast enhanced magnetic resonance imaging can document the normalization of tumor hemodynamics by Nelfinavir, a known radiation sensitizer, and whether this improvement results in an improved response to radiation treatment.